Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.BrC1C(NCC(OC)=O)=NC=C(Br)N=1.C[O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)CN.C(N(C(C)C)CC)(C)C>CS(C)=O>[OH:37][C:38]1[CH:39]=[CH:40][C:43]([C:2]2[N:7]=[C:6]3[N:8]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C:9](=[O:12])[CH2:10][NH:11][C:5]3=[N:4][CH:3]=2)=[CH:44][CH:45]=1
Reactant: COc1cccc(CN2C(=O)CNc3ncc(Br)nc32)c1
Reactant: COc1cccc(CN)c1
Agent: COC(=O)CNc1ncc(Br)nc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN2C(=O)CNc3ncc(-c4ccc(O)cc4)nc32)c1
Yield: 20 %

Procedure:
7-Bromo-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. Methyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (0.58 g, 1.8 mmol), 3-methoxybenzylamine (227 μL, 1.8 mmol), diisopropylethylamine (1 mL), and dimethylsulfoxide (1 mL) were heated to 100° C. for 3 d under nitrogen. The reaction was extracted with ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was purified on silica gel column (0-100% ethyl acetate in hexanes) to give the title compound (124 mg, 20% yield) as a pink solid. MS (ESI) m/z 349.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:3]=1[C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20].ClC1C=C(C=CC=1)C(OO)=[O:31]>ClCCl>[C:13]1([S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([OH:1])=[C:3]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=2)=[O:31])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CNC(=O)c1nc(Sc2ccccc2)c2ccccc2c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1nc(S(=O)c2ccccc2)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as follows: 50 mg of [(4-hydroxy-1-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid, Example D-110, was dissolved in 0.3 ml 1-methyl-2-pyrolydinone and 0.7 ml dichloromethane. The solution was cooled to 0° C. and 26 mg of 75% 3-chloroperoxybenzoic acid was added. The solution was stirred for 2 hours at room temperature, then concentrated under hign vacuum. The resultant residue was triturated with ethyl acetate to provide 32 mg of the product as a white solid; MS (−) m/z 369.08 (M−1)
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)C>O1CCOCC1.O>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH:5]=[O:4])=[CH:9][CH:10]=1
Reactant: CCOC(COc1ccc(CCO)cc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=CCOc1ccc(CCO)cc1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (5 mL) was added to a solution of 2-(4-(2,2-diethoxyethoxy)phenyl)ethanol (example 3, step a) (0.76 g) in 1,4-dioxane (10 mL) and the resulting mixture was stirred for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were washed with water (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound, which was used directly. Yield 0.35 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:10]([C:11]([OH:13])=[O:12])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(F)cc1
Agent: BrCc1cccc(Oc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(F)cc1)C(=O)O

Procedure:
The acid, N-(4-fluorophenyl)valine is prepared as above from 4-fluoroaniline and α-bromoisovaleric acid and then reacted with m-phenoxybenzyl bromide, as above, to yield the m-phenoxybenzyl ester of N-(4-fluorophenyl)valine.
Reaction SMILES: [CH:1]1([CH:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]2[C:15](Cl)=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[N:12][N:11]2[CH:20]=1.CO>CN1C(=O)CCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15]([NH:6][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[N:12][N:11]2[CH:20]=1
Reactant: CC(N)C1CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Yield: 61.9 %

Procedure:
1-Cyclopropylethanamine (93 mg, 1.09 mmol) and 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 100 mg, 0.36 mmol) in NMP (0.5 mL) were heated in the CEM microwave at 120° C. for 10 min. The reaction was allowed to cool to room temperature before the addition of MeOH. The resulting precipitate was then filtered and air dried to afford the title compound (72 mg, 61%). HPLC (condition G): retention time=3.87 min. LCMS (condition B): m/z 323.0, 325.0. 1H NMR (500 MHz, MeOD) δ ppm 8.69 (1 H, d, J=4.99 Hz), 8.40-8.49 (2 H, m), 8.32-8.40 (1 H, m), 8.28 (1 H, s), 7.76 (1 H, td, J=6.59, 1.25 Hz), 7.68 (1 H, d, J=1.94 Hz), 4.12 (1 H, quin, J=6.45 Hz), 1.52 (3 H, d, J=6.38 Hz), 1.14-1.29 (1 H, m), 0.58-0.75 (2 H, m), 0.35-0.51 (2 H, m).
Reaction SMILES: [CH3:1]COCC.[F:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][CH:12]=1.[N+](=C)=[N-]>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:1][CH:14]2[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)/C=C/c1cccc(F)c1
Reactant: CCOCC
Agent: [Pd+2]
Agent: C=[N+]=[N-]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C1CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a flame-dried round-bottom flask containing ether (50 mL) and CH2Cl2 (150 mL) was added 6 (900 mg, 5.0 mmol) and Pd(OAc)2 (5.80 mg) at 0° C. To this flask was added the freshly prepared diazomethane solution through a cannula, and then the reaction solution was slowly warmed to room temperature over a period of 30 min and allowed to stir at room temperature for an additional 2 h. The reaction mixture was washed with H2O (150 mL) and brine (150 mL) and dried over NaSO4. The solvent was removed by rotary evaporation to yield 7 as a colorless oil (965 mg, 5.0 mmol, 100%): 1H NMR (500 MHz, CDCl3) δ 1.30-1.35 (ddd, J=5.0, 7.0, 8.5 Hz, 1H), 1.60-1.66 (dt, J=5.0, 10.0 Hz, 1H), 1.90-1.94 (ddd, J=4.0, 5.0, 8.5 Hz, 1H), 2.51-2.54 (dt, J=2.5, 5.5 Hz, 1H), 3.74 (s, 3H), 6.70-6.80 (td, J=2.0, 10.0 Hz, 1H), 6.90-6.95 (m, 2H), 7.23-7.28 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 17.4, 24.4, 26.1, 52.3, 113.2, 113.4, 113.6, 113.8, 122.2, 130.1, 130.2, 142.9, 143.0, 164.2, 173.8; LCQ-MS (M+H+) calcd for C11H12FO2 195. found 195.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]2)=[O:20])[C:6]([C:9]([O-:11])=[O:10])=[N:7][CH:8]=1.[OH-].[Na+].O.C(OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([F:30])([F:28])[F:29])[CH2:23][CH2:22]2)=[O:20])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1
Reactant: COc1cnc(C(=O)[O-])c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinate (170 mg, 0.37 mmol, EXAMPLE 31 Step 3) in tetrahydrofuran was added 2 N aq. sodium hydroxide (0.5 mL, 1.00 mmol) at room temperature. After being stirred at room temperature for 24 h, water and diethylether were added to the mixture. The aqueous layer was washed with diethylether and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to afford 151 mg (95%) of the title compound as an oil. The residual oil was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.C(OC(N1C[C@@H](S)C[C@H]1CN[C:32]([C:34]1[S:35][C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:38]=1)=[O:33])=O)C=C>C(#N)C>[CH2:42]([O:41][C:39]([C:36]1[S:35][C:34]([C:32](=[O:33])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:38][CH:37]=1)=[O:40])[CH3:43]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNC(=O)c1ccc(C(=O)OCC)s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 90 %

Procedure:
Starting material (12(e)) was prepared as follows. To a stirring solution of 3,4-dichlorobenzylamine (0.53 mL; 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87 g; 4.0 mmole. see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature, under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid (90%).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:27]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][N:35]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)[CH2:36][CH2:37]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 78 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18](O)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(S(F)(F)([F:37])(CC)N)C>C(Cl)Cl>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18]([F:37])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(C(O)(C(=O)OCC)c2ccccc2)n1
Reactant: CCS(N)(F)(F)(F)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)OCC)c2ccccc2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A solution of 2-dodecyl-α-hydroxy-α-phenyl-2H-tetrazole-5-acetic acid, ethyl ester (0.45 g, 1.08 mmole) in CH2Cl2 (2 mL) was added dropwise to a -78° C. solution of diethyl amino sulfur trifluoride (DAST, J. Org. Chem. 1975; (40):574:578, 0.15 mL, 1.1 mmole) in CH2Cl2 (1 mL) under dry nitrogen. The mixture was stirred for 60 minutes at -78° C. before the cooling bath was removed and the solution allowed to warm to room temperature, where it was stirred an additional 3 hours. The mixture was poured into ice water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with brine (50 mL) and dried. Filtration and concentration produced an oil which was flash chromatographed (silica gel, 7:1 hexane-ethyl acetate) to afford 0.3 g (66%) of the title compound as an oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH3:26]>>[C:2]1([O:1][CH2:8][CH2:9][N:10]2[C:11]3[C:20]4[N:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=[C:22]2[CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc2cccnc2c1NCCOc1ccccc1
Reactant: CCCCC(=O)Cl
Product: CCCCc1nc2cnc3cccnc3c2n1CCOc1ccccc1
Yield: 73.5 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine (4.4 g, 15.7 mmol) was reacted with valeryl chloride (1.95 mL, 16.4 mmol) and the resulting amide intermediate was cyclized to provide 4.0 g of 2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether as a white solid; m.p. 150-150.5° C. Analysis: Calculated for C21H22N4O: %C, 72.81; %H, 6.40; %N, 16.17. Found: %C, 72.78; %H, 6.40; %N, 16.31. 1H NMR (300 MHz, DMSO): δ 9.25 (s, 1H), 9.00 (dd, J=4.3,1.7 Hz, 1H), 8.52 (dd, J=8.4,1.7 Hz, 1H), 7.74 (dd, J=8.4,4.3 Hz, 1H), 7.25-7.20 (m, 2H), 6.91-6.84 (m, 3H), 5.22 (t, J=5.2 Hz, 2H), 4.53 (t, J=5.2 Hz, 2H), 3.09 (t, J=7.7 Hz, 2H), 1.91 (pentet, J=7.6 Hz, 2H), 1.55-1.43 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); MS (EI): m/e 346.1794 (346.1793 calc'd for C21H22N4O).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: CN
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Product: CNC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Yield: 70 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using methylamine (2 M solution in THF) instead of isopropylamine, to the title compound (39 mg, 70%) which was obtained as a white solid. MS: m/e=326.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([NH:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.ClC(Cl)(O[C:22](=[O:28])OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:22](=[O:28])[N:16]([CH3:17])[CH:9]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNC(c1ccccn1)c1cc(Br)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 4-Bromo-2-(methylamino-pyridin-2-yl-methyl)-phenylamine (500 mg) in THF (20 mL) is added triphosgene (493 mg, 1.87 mmol), then the mixture is stirred at room temperature for 2 h. TLC showed the reaction is completed. Water (20 mL) is added and the mixture is extracted with EtOAc, the organic layer is dried over Na2SO4 and concentrated to give the desired compound as a crude mixture. This is used in next step with no further purification.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:23][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(Oc2cc(F)cc(F)c2)c(-c2ccccc2)n1
Yield: 16.9 %

Procedure:
6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (101 mg, 17%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3,5-difluorophenol (0.31 g, 3.98 mmol) according to the general procedure of Example 3.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1cccs1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cccs2)CC1
Yield: 10.4 %

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27 mmol), 2-thiophene boronic acid (44 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol), acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 96:4-80:20, biotage 25+S) to yield the a mixture of starting material and product (50 mg, 2:5), along with dehalogenated monochloro starting material (7 mg, 11%). The product/starting material mixture was further purified by preparative hplc (CH3CN, H2O, gradient 1:9 to 9:1, 15 min) to furnish the title compound (9 mg, 10%) as a clear colourless oil, along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (30 mg, 40%) as a white solid, LC-MS (ESI, 4 min) Rt 2.31 min, m/z 322 (100%, [M+H]+); m/z (ESI) C15H16N3OSCl requires 321.0703, found [M+H]+ 321.0700.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:2]=1.F[P-](F)(F)(F)(F)F.[N:24]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:28]2C=CC=[CH:32][C:27]=2N=N1.CCN(C(C)C)C(C)C.C(N)CC>CN(C)C=O>[CH2:28]([NH:24][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[N:16][C:8]=1[O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:27][CH3:32]
Reactant: O=C(O)c1cccnc1Oc1cccnc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cccnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
To a solution of 2-(pyridin-3-yloxy)-nicotinic acid (0.100 g 0.462 mmole), BOP (0.205 grams, 0.463 mmole) and DIEA (0.242 μl) in dimethylformamide (5 ml) was added n-propyl amine (40 μl, 0.486 mmole) and stirred for 4 hours at room temperature. The reaction was quenched with 10 μl water and extracted with ethyl acetate. The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na2SO4, filtered and concentrated to a product which was purified by chromatography on silica gel eluting with diethyl ether to give a white crystalline solid (0.068 g). M.P. 55-56° C.; 1H H NMR (400 mhz, CDCl3) d 0.98 (t, J=7.3 Hz, 3H), 1.61-1.70 (m, 2H), 3.45-3.50 (m, 2H), 7.19 (dd, J=7.5 Hz, 4.8 Hz, 1H), 7.38-7.41 (m, 1H), 7.52-7.55 (m, 1H), 7.72 (bs, 1H), 8.16 (dd, J=4.8 hz, 2.1 Hz, 1H), 8.52-8.63 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:19][NH:18][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C=Cc1ccc(F)cc1)c1cccs1
Solvent: CCO
Solvent: O
Product: Fc1ccc(C2C=C(c3cccs3)NN2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
3-(4-Fluorophenyl)-1-(2-thienyl)-2-propen-1-one (3.5 g, 15 mM) and hydrazine hydrate (1.5 g, 30 mM) were added to ethanol (30 ml) and heated under reflux for 3 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off to obtain 3.6 g (98%) of the desired 5-(4-fluorophenyl)-3-(2-thienyl)-pyrazoline in the form of a pale-yellow oil, nD20=1.6364.
Reaction SMILES: ClCl.[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:20])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4].O.C(Cl)[Cl:23].C(OCC)(=O)C>C(O)(=O)C>[Cl:23][C:18]1[C:11]2[NH:10][C:9](=[O:20])[CH2:8][N:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:13](=[O:14])[C:12]=2[CH:15]=[C:16]([CH3:19])[CH:17]=1
Reactant: Cc1ccc2c(c1)C(=O)N(C(C)(C)C)CC(=O)N2
Reactant: ClCCl
Agent: ClCl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(Cl)c2c(c1)C(=O)N(C(C)(C)C)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorine gas (100 mL, 4.1 mmol) is added via syringe to a mixture of 4-tert-butyl-3,4-dihydro-7-methyl-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.1 mmol) and a few grains of ferric chloride hexahydrate in acetic acid. The reaction mixture is stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water, dilute sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a foam. Flash column chromatography of the foam using silica gel and a 20:1 methylene chloride/ethyl acetate solution gives the title product as a white solid (0.5 g, mp 151°-152° C.).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]=[CH:12][CH:13]2OCC[O:14]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>C(O)C.[Pd]>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][CH2:12][CH:13]=[O:14])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](C=CC2OCCO2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCC[C@H]1CC[C@H](CCC=O)CC1
Temperature: 80 °C

Procedure:
The crude trans-4-butyl-1-[2-(1,3-dioxolan-2-yl)-vinyl]cyclohexane obtained is dissolved in 500 ml of ethanol, treated with 1 ml of triethylamine and 1 g of palladium/carbon (5%) and hydrogenated while shaking. After completion of the hydrogen uptake, the mixture is filtered and the residue is rinsed with 100 ml of ethanol. The filtrate is concentrated to half volume on a rotary evaporator, treated with 300 ml of water and 5 ml of concentrated sulphuric acid and heated to 80° C. for 30 minutes. For the working-up, the mixture is diluted with water, neutralized with sodium hydrogen carbonate and extracted twice with 250 ml of tert.butyl methyl ether each time. The organic phases are dried over sodium sulphate and freed from solvent on a rotary evaporator. The crude product of 3-(trans-4-butylcyclohexyl)propanal obtained is distilled in a high vacuum.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[N:13][C:12]=2[CH3:24])=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([C:11]2[S:15][C:14]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[N:13][C:12]=2[CH3:24])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
Liquid bromine (0.30 g, 0.097 ml, 1.89 mmol) was added drop wise to a stirred solution (5-(4-methoxyphenyl)-4-methylthiazol-2-yl)(piperidin-1-yl)methanone (5a, 0.5 g, 1.58 mmol) in acetic acid (6 ml) at 25° C. The resulting mixture was stirred at 25° C. for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue obtained after concentration was dissolved in ethyl acetate (50 ml). The mixture was then washed with saturated sodium bicarbonate solution (20 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound 5b (0.54 g, 86.0%).